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Interleukin-27 priming of T cells controls Interleukin-17-production in trans via induction of Programmed cell death ligand 1

ABSTRACT: Interleukin (IL)-27 is a key immunosuppressive cytokine that counters T helper 17 (Th17) cell-mediated pathology. To identify mechanisms by which IL-27 might exert its immunosuppressive effect, we analyzed genes in T cells rapidly induced by IL-27. We found that IL-27 priming of naïve T cells upregulated expression of programmed death ligand 1 (PD-L1) in a signal transducer and activator of transcription (STAT)1-dependent manner. When co-cultured with naïve CD4+ T cells, IL-27-primed T cells inhibited the differentiation of Th17 cells in trans through a PD-1-PD-L1 interaction. In vivo, co-administration of naïve TCR transgenic T cells (2D2 T cells) with IL-27-primed T cells expressing PD-L1 inhibited the development of Th17 cells and protected from severe autoimmune encephalomyelitis. Thus, these data identify a suppressive activity of IL-27, by which CD4+ T cells can restrict differentiation of Th17 cells in trans.

ORGANISM(S): Mus musculus

PROVIDER: GSE38375 | GEO | 2012/07/01

SECONDARY ACCESSION(S): PRJNA167754

REPOSITORIES: GEO

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Project description:Our results introduce interleukin (IL)-11 as a new cytokine that may play a role in the development of the autoimmune response in patients with relapsing remitting multiple sclerosis (RR MS). IL-11 was found to be the highest up-regulated cytokine in the serum and cerebrospinal fluid (CSF) from patients with clinically isolated syndrome (CIS) suggestive of MS. It was also increased in the serum and CSF of patients with clinically definitive RRMS and during the clinical relapses of the disease. CD4+ cells represent a predominant cell source of IL-11 in the peripheral circulation, and the percentage of IL-11+CD4+ cells is significantly increased in CIS patients in comparison to healthy controls (HCs). Furthermore, we have identified IL-11 as a new Th17-promoting cytokine. IL-11 induces a differentiation of naïve CD4+ T cells into Th17 cells, as well as Th17 memory cell expansion, characterized by secretion of IL-17A, IL-17F, IL-21 and IL-22. Since the Th17 cytokines IL-17F, IL-21 and TNF- induced differentiation of naïve cells in the IL-11-secreting CD4+ cells, we propose that cross-talk between IL-11+CD4+ and Th17-cells may play a role in the initiation and propagation of the autoimmune response in RRMS. PBMCs were separated from 15 CIS patients and 7 HCs, and the total RNA was extracted and used for gene array hybridization as described previously. To detect differential gene expression profiles between the CIS patients and HCs, a two class paired test of significance analysis was used. In order to capture complex gene expression changes in the PBMCs derived from 15 CIS patients in comparison to 7 HCs, we performed a comprehensive study using Affymetrix Human Gene array U133 (HG-U133) with 45,000 probe sets representing approximately 33,000 human genes. The arrays were hybridized for 16 h at 45oC in a GeneChip® Hybridization Oven 640 (Affymetrix), washed and stained with R-phycoerythrin streptavidin in a GeneChip® Fluidics Station 400 (Affymetrix). The arrays were scanned with a Hewlett Packard GeneArray Scanner. Affymetrix GeneChip® Microarray Suite 5.0 software was used for washing, scanning, and basic analysis. To detect differential gene expression profiles between the CIS patients and HCs, a two class paired test of significance analysis of microarrays was used. Differentially expressed genes were determined using a Welch two sample t-test. A p<0.05 was considered significant.

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Interleukin-27 priming of T cells controls Interleukin-17-production in trans via induction of Programmed cell death ligand 1

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